One of the puzzling questions that becomes more and more apparent as the AIDS epidemic continues is why some people develop AIDS soon after becoming infected with human immunodeficiency virus type-1 (HIV-1) and die quickly, whereas others show no obvious symptoms of the disease and live much longer. There is little doubt that host immune response to HIV-l infection plays a key role in determining the fate of disease progression. However, emerging data also point to a critical role of HIV-1 itself in the disease progression. The purpose of this study is to make detailed comparisons of phenotypic and genotypic variations between virus isolates from the fast progressors and those from the slow progressors among intravenous drug users (IVDUs). In particular, we propose (1) to characterize sequential HIV-1 isolates from 25 seroconverters who developed AIDS in < 5 years and 25 seroconverters who remained healthy for > 5 years matched for calendar time of seroconversion and for initial CD4 counts in the ALIVE cohort. The characterization of phenotypic variations will focus on the ability to kill primary CD4+ T lymphocytes in our recently developed quantitative assay; (2) To compare HIV-1 genetic variations in vivo over time between the 25 rapid progressors and 25 slower progressors. Sequential PBMC samples will be used and will allow us to monitor the virus replication in vivo by measuring the degree of virus sequences variations over time. Studies in this aim will also help us to identify individuals who were infected with the similar virus but had different courses of disease; (3) To study host factors that may influence the disease progression. We will concentrate on a) the role of CD8+ T lymphocyte anti viral response in the low infectious viral load in slower progressors; b) the role of T cell activation (HLA DR and CD38) in virus replication in vivo and disease progression. These studies will provide information that should prove useful in characterizing differences in HIV-1 in pathogenesis between rapid and slower progressors, and should provide useful information for future comparison between IV drug abusers (ALIVE) and individuals who acquire HIV- l infection as a result of sexual transmission (MACS). They should also provide information that may prove critical for the development of candidate preventive and therapeutic HlV strategies.